New crystal modification of torasemide

ABSTRACT

The present invention relates to the characterization of a new crystal modification III of torasemide, to a process for the preparation thereof by the use of controlled acidifying of alkaline solutions of torasemide with inorganic or organic acids with or without addition of a crystal seed, to its use as a raw material for the preparation of the crystal modification I of torasemide and of pharmaceutically acceptable salts of torasemide as well as to pharmaceutical forms containing this new crystal modification III of torasemide.

This is a continuation of application Ser. No. 10/871,667, filed Jun.21, 2004, pending, which is a continuation of application Ser. No.10/096,277, filed Mar. 13, 2002, now U.S. Pat. No. 6,833,379, which is acontinuation of application Ser. No. 09/434,439, filed Nov. 5, 1999, nowU.S. Pat. No. 6,399,637, which is a continuation of application Ser. No.09/187,046, filed Nov. 6, 1998, now abandoned, all of which areincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a new crystal modification ofN-(1-methylethylaminocarbonyl)-4-(3-methyl-phenylamino)-3-pyridinesulfon-amide (in thefurther text of the application designated by its generic name“torasemide”), particularly to a new crystal modification III oftorasemide, to processes for its preparation, to its use as a rawmaterial for the preparation of the crystal modification I of torasemideand of pharmaceutically acceptable salts of torasemide as well as topharmaceutical forms containing the said new modification III oftorasemide as the active ingredient.

BACKGROUND OF INVENTION

Torasemide is a compound with interesting pharmacological properties,which is described in DE patent 25 16 025 (Example 71). As a diuretic ofHenle's loop it is useful as an agent for preventing heart or hearttissue damages caused by metabolic or ionic abnormalities associatedwith ischemia, in the treatment of thrombosis, angina pectoris, asthma,hypertension, nephroedema, pulmonary edema, primary and secondaryaldosteronism, Bartter's syndrome, tumours, glaucoma, decreasing ofintraocular pressure, acute or chronic bronchitis, in the treatment ofcerebral edema caused by trauma, ischemia, concussion of the brain,metastases or epileptic attacks and in the treatment of nasal infectionscaused by allergens.

The ability of a substance to exist in more than one crystal form isdefined as polymorphism and these different crystal forms are named“polymorph modifications” or “polymorphs”. In general, polymorphism isaffected by the ability of a molecule of a substance to change itsconformation or to form different intermolecular or intra-molecularinteractions, particularly hydrogen bonds, which is reflected indifferent atom arrangements in the crystal lattices of differentpolymorphs. Polymorphism is found in several organic compounds. Amongmedicaments polymorphism is found in about 70% of barbiturates, 60% ofsulfonamides and 60% of steroids and about 50% of medicaments of thesaid classes are not present on the market in their most stable forms(T. Laird, Chemical Development and Scale-up in the Fine ChemicalIndustry, Principles and Practices, Course Manual, Scientific Update,Wyvern Cottage, 1996).

The different polymorphs of a substance possess different energies ofthe crystal lattice and, thus, in solid state they show differentphysical properties such as form, density, melting point, colour,stability, dissolution rate, milling facility, granulation, compactingetc., which in medicaments may affect the possibility of the preparationof pharmaceutical forms, their stability, dissolution andbioavailability and, consequently, their action.

Polymorphism of medicaments is the object of studies of interdisciplinarexpert teams [J. Haleblian, W. McCrone, J. Pharm. Sci. 58 (1969) 911; L.Borka, Pharm. Acta Helv. 66 (1991) 16; M. Kuhnert-Brandsttter, Pharmazie51 (1996) 443; H. G. Brittain, J. Pharm. Sci. 86 (1997) 405; W. H.Streng, DDT 2 (1997) 415; K. Yoshii, Chem. Pharm. Bull. 45 (1997) 338,etc.] since a good knowledge of polymorphism represents a preconditionfor a critical observation of the whole process of medicamentdevelopment. Thus, at deciding on the production of a pharmaceuticalform in solid state and with regard to the dose size, stability,dissolution and anticipated action, it is necessary to determine theexistence of all solid state forms (on the market some computerprogrammes can be found, e.g. >>Polymorph<<as a moduleof >>Cerius2<<programme, MSI Inc., USA) and to determine the stability,dissolution and thermodynamic properties of each of them. Only on thebasis of these determinations the appropriate polymorph can be selectedfor the development of pharmaceutical formulations.

From the great number of such efforts only a few will be mentioned.Thus, Gordon et al. (U.S. Pat. No. 4,476,248) protected a new crystalform of ibuprofen and a process for the preparation thereof; Bunnell etal. (EP 733 635) protected a new crystal form, a process for preparationthereof and a pharmaceutical formulation of the medicament olanzapinecontaining this new crystal form; R. B. Gandhi et al. (EP 749 969)protected a new process for the preparation of polymorph form I ofstavudine from a mixture of one or more forms I, II and III; A. Caron etal. (EP 708 103) protected a new crystal form of irbesartane, a processfor the preparation thereof and pharmaceutical formulations containingthis crystal form.

It is known [Acta Cryst. B34 (1978), 2659-2662 and Acta Cryst. B34(1978), 1304-1310] that torasemide can exist in two crystalmodifications differing with regard to the parameters of a single cell,which is confirmed by X-ray diffraction on their monocrystals. Bothmodifications are formed simultaneously by the slow evaporation of thesolvent from a solution of torasemide in a mixture petroleumether/ethanol. The modification I with melting point 169° C.crystallizes monoclinically in the space group P 2₁/c (prisms), whilethe modification II with melting point 162° C. crystallizesmonoclinically in the space group P 2/n (foils). Additionally, for themodification I the melting point 169.22° C. is stated in Iyakuhin Kenkyu25 (1994), 734-750.

According to Example 71 of DE 25 16 025 torasemide in a crystal formwith melting point 163-164° C. is obtained.

In U.S. Pat. No. 4,743,693 and U.S. Pat. No. reissue 34,580 or U.S. Pat.No. 4,822,807 and U.S. Pat. No. reissue 34,672 there is disclosed aprocess for the preparation of a stable modification I of torasemidefrom an unstable modification II of torasemide by adding a catalyticamount (1%) of a stable modification I of torasemide into a suspensionof the unstable modification in water and stirring the mixture at atemperature from room temperature to 90° C. within 3 hours to 14 days.In U.S. Pat. No. 4,743,693 and US reissue 34,580 it is stated that thestable modification I of torasemide (monoclinic, space group P 2₁/c) hasa melting point of 162° C. and the unstable modification II oftorasemide (monoclinic, space group P 2/n) has a melting point 169° C.,which is contrary to the statements in Acta Cryst. B34 (1978),2659-2662, Acta Cryst. B34 (1978), 1304-1310 and Iyakuhin Kenkyu 25(1994), 734-750.

In the abstract of U.S. Pat. No. 4,822,807 the authors ascribe themelting point 162° C. to the stable polymorph I of torasemide and themelting point 169° C. to the unstable polymorph II of torasemide,whereas in the claims of the said patent different melting points foreither polymorph are stated, namely for polymorph I the melting point169° C. and for polymorph II the melting point 162° C.

In the abstract of U.S. Pat. No. reissue 34,672 the authors ascribe themelting point 162° C. to the pure modification I of torasemide and themelting point 169° C. to the modification II of torasemide, whereas inthe claims the melting point 159-161.5° C. for the pure polymorph I andthe melting point from about 157.5 to about 160° C. for the unstablepolymorph II are stated.

SUMMARY OF INVENTION

It has now been surprisingly found that by a controlled acidifying ofalkaline solutions of torasemide with inorganic or organic acids with orwithout addition of a seed crystal at a temperature between 0 and 35° C.within 15 minutes to 25 hours, a new crystal modification III oftorasemide can be prepared.

By the alkaline solutions of torasemide according to the process of thepresent invention there are meant an alkaline extract of the originalreaction mixture for the synthesis of torasemide, alkaline solutions ofany crystal modification I, II or III of torasemide or alkalinesolutions of any mutual mixtures of crystal modifications I, II or IIIof torasemide.

In the process of the present invention for the preparation of alkalinesolutions of torasemide modifications, water solutions of lithium,sodium and potassium hydroxide as well as water solutions of sodium andpotassium carbonate can be used.

The acidifying of the alkaline torasemide solutions according to theinvention can be performed in inorganic acids such as hydrochloric,sulfuric, phosphoric and nitric acids and in organic acids such asformic, acetic, propionic, oxalic, tartaric, methanesulfonic andp-toluenesulfonic acids.

As the seed crystal in the processes of the present invention crystalpowder of one of the isostructure substances, particularly crystalpowder of the crystal modification III of torasemide can be used.

It has additionally been found that by using the process of the presentinvention no decomposition of torasemide occurs and the impurities thatmay be present in the alkaline extract of the original reaction mixturefor the synthesis of torasemide or in modifications I, II or III oftorasemide pass, by the present process, into bases, i.e. a chemicallypure crystal modification III of torasemide is obtained.

Moreover, it has been found that the new crystal modification III oftorasemide is stable under normal storage conditions as well as at beingsubjected to increased humidity, which means that it is neithertransformed into the unstable modification II of torasemide nor into thestable modification I of torasemide.

The new crystal modification III of torasemide has a characteristicX-ray powder pattern obtained by X-ray diffraction on a powder sample ofthe new crystal modification III of torasemide in the instrument PHILIPSPW3710 under Cu X-rays [.lambda. (CuKα₁)=1.54046 Å. λ(CuKα₂)=1.54439 Å].Thus obtained characteristic spacings between lattice planes designatedby )>>d<<and expressed in Angström units and their correspondingcharacteristic relative intensities designated by >>I/I₀<<and expressedin % are represented in Table 1. TABLE 1 Modification III d(Å) I/I₀ (%)15.3898 2.8 12.5973 5.4 11.4565 5.8 9.7973 69.8 9.5493 76.6 8.6802 28.58.2371 100.0 7.6351 10.2 7.3356 13.0 6.9759 1.2 6.5351 10.0 6.3240 7.96.1985 4.5 5.9521 0.6 5.6237 24.4 5.5623 29.7 5.4040 19.6 5.1119 10.34.8738 22.7 4.7865 46.9 4.6986 45.7 4.5985 17.9 4.4602 24.7 4.3405 90.04.2552 20.7 4.1829 19.9 4.0768 19.9 3.9377 47.1 3.8659 29.3 3.8429 35.33.7801 42.8 3.7248 11.9 3.6239 31.7 3.5556 20.5 3.4825 7.8 3.4130 8.13.3055 15.5 3.2298 8.2 3.1786 10.7 3.1278 5.6 3.0699 7.1 3.0078 17.52.9549 5.1 2.9056 4.3 2.8541 1.8 2.7686 13.9 2.6988 5.7 2.6610 6.32.6293 7.3 2.5549 3.7 2.5236 2.0 2.4485 5.3 2.4161 6.7 2.3671 2.0 2.31333.6 2.2788 7.6 2.2312 3.4 2.1852 6.2 2.1468 3.0 2.0957 4.7 2.0617 4.12.0273 3.3 1.9896 3.1 1.9688 4.1 1.9274 2.6 1.8853 2.7 1.7931 2.1 1.74491.0 1.7169 1.8 1.6512 1.0 1.6122 0.8 1.5601 0.8 1.5320 0.3 1.5057 0.51.4521 0.3 1.3773 0.6

In addition, by recording the monocrystal of the new crystalmodification III of torasemide in four circle PHILIPS PW 1100/Stoe&Ciediffractometer under Mo X-rays [λ (MoKα)=0.71073 Å] there were obtainedthe basic crystallographic data for a single cell, which show incomparison with the literature data for crystal modifications I and IIof torasemide [Acta Cryst. B34 (1978), 2659-2662 and Acta Cryst. B34(1978), 1304-1310] that this is an absolutely new crystal modificationIII of torasemide.

The basic crystallographic data (diffraction on monocrystal) formodifications I, II and the new crystal modification III of torasemideare represented in Table 2. TABLE 2 Crystal modification of torasemideParameter I II III Crystal composition monoclinic Monoclinic monoclinicspace group P 2₁/c P 2/n P 2₁/c a (Å) 13.308 20.446 11.430 b (Å) 8.22311.615 19.090 c (Å) 31.970 16.877 16.695 β (°) 107.01 108.90 93.903 V(Å³) 3345.5 3791.9 3634.7 Z 4 × 2 4 × 2 4 × 2

The new crystal modification III of torasemide prepared according to theprocess of the present invention can be transformed by the use of commonprocesses to the crystal modification I of torasemide, i.e. it can beused as a starting material for the preparation of known crystalmodification I of torasemide.

The new crystal modification III of torasemide prepared according to theinvention can be transformed to pharmaceutically acceptable salts oftorasemide by the use of common processes.

The dissolution profile (U.S. Pat. No. 23) of the new crystalmodification III of toresamide in water and in artificial intestinaljuice in comparison to dissolution profiles of known crystalmodifications I and II of torasamide, in the same fluids, shows asignificant difference.

IDR (Intrinsic Dissolution Rate) of the new crystal modification III oftorasemide in a model of artifical gastric juice exceeds 1 mg cm⁻²min³¹¹, which indicates a potential good bioavailability.

The new crystal modification III of torasemide is prepared according tothe process of the present invention in the form of a flowable crystalpowder of a prismatic habitude, which exhibits flowability, i.e. itcomes in a “free flow” form, wherein no static charge accumulationoccurs.

The new crystal modification III of torasemide prepared according to theprocess of the present invention can be used as a suitable torasemideform as a diuretic as well as an agent for preventing heart or hearttissue damages caused by metabolic or ionic abnormalities associatedwith ischemia, in the treatment of thrombosis, angina pectoris, asthma,hypertension, nephroedema, pulmonary edema, primary and secondaryaldosteronism, Bartter's syndrome, tumours, glaucoma, for decreasingintraocular pressure, acute or chronic bronchitis, in the treatment ofcerebral edema caused by trauma, ischemia, concussion of the brain,metastases or epileptic attacks and in the treatment of nasal infectionscaused by allergens.

The present invention also relates to pharmaceutical forms such astablets containing the new crystal modification III of torasemide as theactive ingredient combined with one or more pharmaceutically acceptableadditives such as sugar, starch, starch derivatives, cellulose,cellulose derivatives, mould release agents, and antiadhesive agents andpossibly agents for flowability regulation. When using the new crystalmodification III of torasemide for the preparation of pharmaceuticalforms, also process steps taking place in water, e.g. granulation, canbe used.

The starting materials for the process of the present invention i.e. thealkaline extract of the original reaction mixture for torasemidesynthesis can be prepared according to DE 25 16 025, whereas themodifications I and II of torasemide can be prepared according to ActaCryst. B34 (1978), 1304-1310.

SUMMARY OF DRAWINGS

FIG. 1 is a graph of dissolution tests of torasemide in water.

FIG. 2 is a graph of dissolution tests of torasemide in artificialintestinal juice.

BEST AND VARIOUS MODES FOR CARRYING OUT INVENTION

The present invention is illustrated but in no way limited by thefollowing Examples.

EXAMPLE 1

Technically Pure New Crystal Modification III of Torasemide

The original alkaline extract of the reaction mixture for torasemidesynthesis (1000 ml) prepared according to DE 25 16 025 was acidifiedwith 10% aqueous acetic acid solution under the addition of 1.4 g of acrystal modification III of torasemide. The suspension was stirred atroom temperature for 90 minutes. The crystals were sucked off, washedwith 1 litre of demineralized water and dried in a vacuum dryer at 50°C. for 3 hours. There were obtained 125 g of a crystal modification IIIof torasemide, m.p. 162-165° C.

The X-ray powder pattern of the thus obtained sample corresponded to thenew crystal modification III of torasemide. The content of torasemideaccording to the HPLC method was>99%.

EXAMPLE 2

The crystal modification III of torasemide (1000 g) prepared accordingto the Example 1 was dissolved in a 10-fold amount of 5% aqueouspotassium hydroxide solution and at the temperature of 20° C. theobtained solution was acidified with 5% aqueous hydrochloric acidsolution under the addition of 10 g of a crystal modification III oftorasemide. The suspension was stirred at 20° C. for 120 minutes. Thecrystals were sucked off, washed with 4 litres of demineralized waterand dried in a vacuum dryer at 50° C. for 3 hours. There were obtained961 g of a modification III of torasemide, m.p. 165° C.

The X-ray powder pattern of the thus obtained sample corresponded to thecrystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasermide.

EXAMPLE 3

The crystal modification I of torasemide (1.00 g) prepared according toActa Cryst. B34 (1978), 1304-1310 was dissolved in a 10-fold amount of10% aqueous sodium carbonate solution and at the temperature of 15° C.the obtained solution was acidified with 5% aqueous sulfuric acidsolution under the addition of 0.10 g of the modification III oftorasemide. The suspension was stirred at 15° C. for 120 minutes. Thecrystals were sucked off, washed with 4 ml of demineralized water anddried in a vacuum dryer at 50° C. for 3 hours. There were obtained 0.95g of a crystal modification III of torasemide, m.p. 165-166° C.

The X-ray powder pattern of the thus obtained sample corresponded to thecrystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 4

The crystal modification II of torasemide (1.00 g) prepared according toActa Cryst. B34 (1978), 1304-1310 was dissolved in a 10-fold amount of10% aqueous potassium carbonate solution and then at the temperature of15° C. the obtained solution was acidified with 5% aqueous nitric acidsolution under the addition of 0.10 g of a modification III oftorasemide. The suspension was stirred at 15° C. for 120 minutes. Thecrystals were sucked off, washed with 4 ml of demineralized water anddried in a vacuum dryer at 50° C. for 3 hours. There were obtained 0.96g of a crystal modification III of torasemide, m.p. 164-166° C.

The X-ray powder pattern of the thus obtained sample corresponded to thecrystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 5

A mixture of crystal modifications I and II of torasemide (1.00 g)prepared according to Acta Cryst. B34 (1978), 1304-1310 was dissolved ina 10-fold amount of 10% aqueous lithium hydroxide solution and then atroom temperature the obtained solution was acidified with 5% aqueousphosphoric acid solution under the addition of 0.10 g of a modificationIII of torasemide. The suspension was stirred at 15° C. for 240 minutes.The crystals were sucked off, washed with 4 ml of demineralized waterand dried in a vacuum dryer at 50° C. for 3 hours. There were obtained0.97 g of a crystal modification III of torasemide, m.p. 165-166° C.

The X-ray powder pattern of the thus obtained sample corresponded to thecrystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 6

A mixture of crystal modifications I and III of torasemide (1.00 g)prepared according to Acta Cryst. B34 (1978), 1304-1310 and Example 1was dissolved in a 10-fold amount of 5% aqueous potassium hydroxidesolution and then at the temperature of 30° C. the obtained solution wasacidified with 10% aqueous tartaric acid solution under the addition of0.10 g of a modification III of torasemide. The suspension was stirredat 30° C. for 180 minutes. The crystals were sucked off, washed with 4ml of demineralized water and dried in a vacuum dryer at 50° C. for 3hours. There were obtained 0.93 g of a crystal modification III oftorasemide, m.p. 164-166° C.

The X-ray powder pattern of the thus obtained sample corresponded to thecrystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 7

A mixture of crystal modifications II and III of torasemide (1.00 g)prepared according to Acta Cryst. B34 (1978), 1304-1310 and Example 1was dissolved in a 10-fold amount of 5% aqueous sodium hydroxidesolution and then at the temperature of 35° C. the obtained solution wasacidified with 5% aqueous propionic acid solution under the addition of0.10 g of a modification III of torasemide. The suspension was stirredat 35° C. for 90 minutes. The crystals were sucked off, washed with 4 mlof demineralized water and dried in a vacuum dryer at 50° C. for 3hours. There were obtained 0.87 g of a crystal modification III oftorasemide, m.p. 165° C.

The X-ray powder pattern of the thus obtained sample corresponded to thecrystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 8

A mixture of crystal modifications I, II and III of torasemide (1.00 g)prepared according to Acta Cryst. B34 (1978), 1304-1310 and Example 1was dissolved in a 10-fold amount of 10% aqueous sodium carbonatesolution and then at the temperature of 25° C. the obtained solution wasacidified with 5% aqueous p-toluenesulfonic acid solution under theaddition of 0.10 g of a modification. III of torasemide. The suspensionwas stirred at 25° C. for 60 minutes. The crystals were sucked off,washed with 4 ml of demineralized water and dried in a vacuum dryer at50° C. for 3 hours. There were obtained 0.93 g of a crystal modificationIII of torasemide, m.p. 164-166° C.

The X-ray powder pattern of the thus obtained sample corresponded to thecrystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 9

A crystal modification I of torasemide (1.00 g) prepared according toActa Cryst. B34 (1978), 1304-1310 was dissolved in a 10-fold amount of10% aqueous potassium carbonate solution and then at the temperature of15° C. the obtained solution was stepwise acidified with 10% aqueousacetic acid solution under the simultaneous stepwise lowering of thetemperature of the mixture to 0° C. At this temperature the suspensionwas stirred for 25 hours. The crystals were sucked off, washed with 4 mlof demineralized water and dried in a vacuum dryer at 50° C. for 3hours. There were obtained 0.94 g of a crystal modification III oftorasemide, m.p. 164-166° C.

The X-ray powder pattern of the thus obtained sample corresponded to thecrystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 10

Production of 2.5 mg Tablets

Torasemide of the crystal modification III was mixed with lactose andcorn starch in a common manner, granulated with water, dried and sieved(granulate 1). Colloidal silicon dioxide and magnesium stearate weremixed, sieved and admixed into granulate 1. This mixture was thentabletized in a common manner. For the production of 100 000 tablets thefollowing is required: 3 torasemide-crystal modification III 0.25 kglactose (Lactose Extra Fine Crystal HMS ®) 6.05 kg corn starch(Starch ®) 1.60 kg colloidal silicon dioxide (Aerosil 200 ®) 60.00 gmagnesium stearate 40.00 g redistilled water 1.20 kg

EXAMPLE 11

Production of 100 mg Tablets

Torasemide of crystal modification III was mixed with lactose and cornstarch and a part of magnesium stearate in a common manner. The mixturewas compressed and sieved to obtain the desired grain size anddistribution of grain size (granulate 1 ). Colloidal silicon dioxide andmagnesium stearate were mixed, sieved and admixed into granulate 1. Thismixture was then tabletized in a common manner. For the production of100 000 tablets the following is required: 4 torasemide-crystalmodification III 10.0 kg  lactose (Lactose Extra Fine Crystal HMS ®) 2.0kg corn starch (Starch ®) 7.7 kg colloidal silicon dioxide (Aerosil200 ®) 0.2 kg magnesium stearate 0.1 kg

EXAMPLE 12

The microcrystallinic modifications I, II and III of torasemide preparedaccording to Acta Crst. B34 (1978), 1304-1310 and Example 1 weresubjected to dissolution testing in water, and in artificial intestinaljuice, at 37° C. (U.S. Pat. No. 23), and results are reported in tables3 and 4. TABLE 3 Dissolution test of torasemide in water (USP 23) (37°C., 50 rpm., 1000 ml) % Dissolved torasemide Munutes Mod. I Mod. II ModIII 0 0 0 0 10 6.7 15.1 15.6 20 13.0 27.8 28.1 30 18.5 39.2 37.7 40 23.548.8 43.6 50 28.5 56.3 48.5 60 32.8 65.1 51.1

TABLE 4 Dissolution test of torasemide in artificial intestinal juice(USP 23) (37° C., 50 rpm., pH 7.5, 1000 ml) % Dissolved torasemideMunutes Mod. I Mod. II Mod III 0 0 0 0 10 29.4 73.3 41.0 20 40.5 92.659.8 30 48.4 95.5 70.2 40 54.2 96.8 77.6 50 59.2 96.3 82.5 60 65.0 98.288.7

The results reported in Table 3 were plotted in the FIG. 1. The resultsreported in Table 4 were plotted in the FIG. 2.

1. New crystal modification III of torasemide, characterized in that thecharacteristic X-ray powder pattern of its sample is represented by thefollowing spacings between lattice planes: New crystal modification IIIof torasemide d(Å) 15.3898 12.5973 11.4565 9.7973 9.5493 8.6802 8.23717.6351 7.3356 6.9759 6.5351 6.3240 6.1985 5.9521 5.6237 5.5623 5.40405.1119 4.8738 4.7865 4.6986 4.5985 4.4602 4.3405 4.2552 4.1829 4.07683.9377 3.8659 3.8429 3.7801 3.7248 3.6239 3.5556 3.4825 3.4130 3.30553.2298 3.1786 3.1278 3.0699 3.0078 2.9549 2.9056 2.8541 2.7686 2.69882.6610 2.6293 2.5549 2.5236 2.4485 2.4161 2.3671 2.3133 2.2788 2.23122.1852 2.1468 2.0957 2.0617 2.0273 1.9896 1.9688 1.9274 1.8853 1.79311.7449 1.7169 1.6512 1.6122 1.5601 1.5320 1.5057 1.4521 1.3773


2. New crystal modification III of torasemide according to claim 1,characterized in that in accordance with X-ray diffraction on its samplemonocrystal it is represented by the following basis crystallographicdata: New crystal modification of Parameter torasemide Crystalcomposition monoclinic space group P 2₁/c a (Å) 11.430 b (Å) 19.090 c(Å) 16.695 β (°) 93.903 V (Å³) 3634.7 Z 4 × 2


3. New crystal modification III of torasemide according to claim 1,characterized in that it is chemically pure.
 4. New crystal modificationIII of torasemide according to claim 1, characterized in that it doesnot contain water.
 5. New crystal modification III of torasemideaccording to claim 1, characterized in that it does not contain asolvent.
 6. Process for the preparation of a new crystal modificationIII of torasemide according to claim 1, characterized in that analkaline torasemide solution is subjected to controlled acidifying withinorganic or organic acids with or without addition of a seed crystal ata temperature between 0° C. to 35° C. within 15 minutes to 25 hours. 7.Process for the preparation of a new crystal modification III oftorasemide according to claim 6, characterized in that as the alkalinetorasemide solution an alkaline extract of the original reaction mixturefor the synthesis of torasemide is used.
 8. Process for the preparationof a new crystal modification III of torasemide according to claim 6,characterized in that as the alkaline torasemide solution an alkalinesolution of any crystal modification I, II or III of torasemide or analkaline solution of any mutual mixture of crystal modifications I, IIor III of torasemide is used.
 9. Process according to claim 6,characterized in that for the preparation of the alkaline torasemidesolutions water solutions of lithium, sodium and potassium hydroxide andwater solutions of sodium and potassium carbonate are used.
 10. Processaccording to claim 6, characterized in that for acidifying inorganicacids such as hydrochloric, sulfuric, phosphoric or nitric acid ororganic acids such as formic, acetic, propionic, oxalic, tartaric,methanesulfonic or p-toluensulfonic acid are used.
 11. Process accordingto claim 6, characterized in that as the crystal seed crystal powder ofone of the isocrystallinic substances is used, most preferably crystalpowder of a crystal modification III of torasemide.
 12. A new crystalmodification III of torasemide according to claim 1, characterized inthat it is used as a raw material for the preparation of crystalmodification I of torasemide.
 13. A new crystal modification III oftorasemide according to claim 1, characterized in that it is used as araw material for the preparation of pharmaceutically acceptable salts oftorasemide.
 14. A new crystal modification III of torasemide accordingto claim 1, characterized in that it is used as a form of torasemide asa diuretic, as an agent for preventing heart or heart tissue damagescaused by metabolic or ionic abnormalities associated with ischemia, inthe treatment of thrombosis, angina pectoris, asthma, hypertension,nephroedema, pulmonary edema, primary and secondary aldosteronism,Bartter's syndrome, tumours, glaucoma, for decreasing intraocularpressure, acute or chronic bronchitis, in the treatment of cerebraledema caused by trauma, ischemia, concussion of the brain, metastases orepileptic attacks and in the treatment of nasal infections caused byallergens.
 15. A pharmaceutical form, characterized in that it containsas the active ingredient the new crystal modification III of torasemideaccording to claim 1 combined for this purpose with pharmaceuticallyacceptable one or more carriers, additives or diluents.
 16. Apharmaceutical form according to claim 15, characterized in that it isin tablet form.